Childhood Vascular Tumors Treatment (PDQ®)

Last Modified : 2018-01-26

General Information About Childhood Vascular Tumors

Vascular anomalies are a spectrum of rare diseases classified as vascular tumors or malformations. An updated classification system was adopted at the General Assembly of the International Society for the Study of Vascular Anomalies (ISSVA, April 2014) and recently published.
[1]
Generally, vascular tumors are proliferative, while malformations enlarge through expansion of a developmental anomaly without underlying proliferation.

Limited treatment options are available; their efficacy has not been validated in prospective clinical trials. Historically, therapies have been mostly interventional and surgical to palliate symptoms. New drugs such as propranolol and sirolimus are now available for the treatment of patients with some of these complex conditions. The first prospective clinical trial using propranolol for infantile hemangioma has been published, as well as the first prospective clinical trial that studied the effectiveness of sirolimus for complicated vascular anomalies.
[2]
[3]

With a prevalence of 4% to 5%, infantile hemangiomas are the most common benign tumors of infancy. Other vascular tumors are rare. The classification of these tumors has been difficult, especially in the pediatric population, because of their rarity, unusual morphologic appearance, diverse clinical behavior, and the lack of independent stratification for pediatric tumors. In 2013, The World Health Organization (WHO) updated the classification of soft tissue vascular tumors. Pediatric tumors were not independently stratified and the terminology was mostly left unchanged, but the intermediate category of tumors was divided into locally aggressive and rarely metastasizing. The ISSVA classification of tumors is based on the WHO classification (refer to Tables 1 and 2) but the ISSVA classification uses more precise terminology and phenotypes that have been agreed upon by the members of ISSVA.

International Society for the Study of Vascular Anomalies: ISSVA Classification for Vascular Anomalies. Melbourne, Australia: International Society for the Study of Vascular Anomalies, 2014. Available online. Last accessed August 31, 2017.[PUBMED Abstract]

Infantile Hemangioma

Incidence and epidemiology

Infantile hemangiomas (IH) are the most common benign vascular tumor of infancy, occurring in 4% to 5% of infants. They are not usually present at birth and are diagnosed most commonly at age 3 to 6 weeks.
[1]
[2]
[3]
The lesion proliferates for an average of 5 months, stabilizes, and then involutes over several years.

Infantile hemangiomas are more common in females, non-Hispanic white patients, and premature infants. Multiple hemangiomas are more common in infants who are the product of multiple gestations.
[1]
[4]
Infantile hemangiomas are associated with advanced maternal age and placental complications.
[1]

Biology

Most infantile hemangiomas occur sporadically. However, they may rarely be caused by an abnormality of chromosome 5 and present in an autosomal dominant pattern.
[5]
In a study that evaluated inheritance patterns of infantile hemangiomas, 34% of patients had a family history of infantile hemangioma, most commonly in a first-degree relative.
[6]

Infantile hemangioma endothelial cells have proven to be clonal in nature.
[7]
[8]
Infantile hemangioma proliferation occurs during vasculogenesis (the formation of new blood vessels from angioblasts), as opposed to angiogenesis (the formation of new blood vessels from existing blood vessels). During proliferation, provasculogenic factors are expressed, such as vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), CD34, CD31, CD133, LYVE-1, and insulin-like growth factor (IGF)-2.
[9]
[10]
[11]
[12]
In involution, infantile hemangiomas express increased apoptosis.
[12]
During this phase, there are also increased mast cells and levels of metalloproteinase, as well as upregulation of interferon and decreased basic FGF (bFGF).
[12]
[13]
[14]
Throughout their development, endothelial cells in infantile hemangioma express a particular phenotype showing positive staining for glucose transporter (GLUT1). GLUT1 is also expressed on placental endothelial cells but is absent in other vascular tumors such as congenital hemangioma and vascular malformations.
[15]

Hypoxia may have a role in the pathogenesis of hemangiomas. As described above, hemangiomas are associated with conditions related to placental hypoxia,
[1]
and multiple targets of hypoxia
[16]
[17]
are demonstrated in proliferating hemangiomas such as VEGF-A, GLUT1, and IGF-2.
[9]
[11]
[15]
The hypotheses suggest that a proliferating hemangioma is an attempt to normalize hypoxic tissue that occurred in utero.

Clinical presentation

Most infantile hemangiomas are not present at birth but precursor lesions such as telangiectasia or faint discoloration of the skin or hypopigmentation can often be seen. The lesion can be mistaken as a bruise from birth trauma or as a capillary malformation (port wine stain) (refer to Figure 1).
[18]
[19]

Figure 1. The photos on the left depict the precursor lesion (faint color with halo). The photos on the right depict the hemangioma after proliferation (slightly raised with a brighter central color). Credit: Israel Fernandez-Pineda, M.D.

Infantile hemangiomas can be superficial in the dermis, deep in the subcutaneous tissue, combined, or in the viscera. Combined lesions are common. They are most common in the head and neck but can be anywhere on the body. They can be localized, segmental, or multiple in nature.

The cutaneous appearance of infantile hemangiomas is usually red to crimson, firm, and warm in the proliferative phase. The lesion then lightens centrally and becomes less warm and softer; it then flattens and loses its color. The process of involution can take several years and once involution has occurred, regrowth is uncommon. In two patients treated with growth hormone, regrowth after involution was noted.
[20]
On further investigation, growth hormone receptors were found on the infantile hemangioma cells. Although preliminary, this may advance the research into the etiology of hemangioma growth.

Permanent sequelae, such as telangiectasia, anetodermal skin, redundant skin, and a persistent superficial component, can occur after hemangioma involution (refer to Figure 2). In a retrospective cohort study of 184 hemangiomas, the overall incidence of significant sequelae was 54.9%. Sequelae were more common in combined hemangiomas, hemangiomas with a step or abrupt border, and cobblestone surface hemangiomas. Furthermore, this study revealed that the average age to hemangioma involution was 3.5 years.
[21]

Diagnostic and staging evaluation

Infantile hemangiomas are usually diagnosed by the history and clinical appearance. Biopsy is rarely needed and performed only if there is an atypical appearance and/or atypical history and presentation. Imaging is not usually necessary, but if there is a deeper lesion without a cutaneous component, ultrasound imaging is beneficial for diagnosis because it reveals a high flow lesion with a typical Doppler wave characteristic.
[22]

Infantile hemangioma with minimal or arrested growth

Infantile hemangioma with minimal or arrested growth (IH-MAG) is a variant of hemangioma that can be confused with capillary malformation or other syndromic hemangioma, such as PHACE syndrome, because of their unusual characteristics. These hemangiomas are mostly fully formed at birth and are characterized by telangiectasia and venules with light and dark areas of skin coloration (refer to Figure 3). They resolve spontaneously and are pathologically GLUT1 positive.
[23]

Airway infantile hemangioma

Airway infantile hemangiomas are usually associated with segmental hemangiomas in a bearded distribution, which may include all or some of the following—the preauricular skin, mandible, lower lip, chin, or anterior neck. Airway infantile hemangioma can occur without skin lesions. It is important for an otolaryngologist to proactively assess lesions in this distribution before signs of stridor occur. The incidence of an airway infantile hemangioma increases with increased area of bearded involvement.
[24]

Periorbital infantile hemangioma

Periorbital hemangiomas can cause visual compromise.
[25]
This usually occurs with hemangiomas of the upper medial eyelid but any hemangioma around the eye that is large enough can obstruct the visual axis. The clinician should be aware of subcutaneous periocular hemangiomas, as these lesions can extend into the orbit, causing exophthalmos or globe displacement with only limited cutaneous manifestations. Issues with these lesions include astigmatism from direct pressure of the growing hemangioma, ptosis, proptosis, and strabismus. One of the leading causes of preventable blindness in children is stimulus-deprivation amblyopia caused by hemangioma obstruction. All periorbital hemangiomas or those with any possibility of potential visual impairment should have an ophthalmologic evaluation.

Syndromes associated with infantile hemangioma

Syndromes associated with infantile hemangioma include the following:

PHACE syndrome:

PHACE syndrome represents a spectrum of diseases and is defined by the presence of a large segmental infantile hemangioma, usually on the face or head, in association with one or more congenital malformations (refer to Figure 4). PHACE syndrome is more common in girls and in full-term, normal birth weight and singleton infants.
[26]
[27]
[28]
[29]
[30]
[31]
[31]
The syndrome is not rare among patients with infantile hemangiomas. A prospective study of 108 infants with large facial hemangiomas observed that 31% of patients had PHACE syndrome.
[32]

Figure 4. A large segmental infantile hemangioma (plaque-like) in a bearded distribution. This patient has an increased risk of PHACE syndrome, airway infantile hemangioma, and ulceration. A tracheostomy was placed secondary to a very diffuse airway hemangioma. Credit: Denise Adams, M.D.

Consensus criteria for definite and possible PHACE syndrome were developed at an expert panel meeting, as follows:
[28]

PHACE

P

osterior fossa abnormalities. Anomalies include posterior fossa malformations, including Dandy-Walker complex, cerebellar hypoplasia, atrophy, and dysgenesis/agenesis of the vermis. Effects of these anomalies include developmental delays and pituitary dysfunction.
[33]

H

emangioma. A large segmental hemangioma over the face, neck, and rarely, the chest and shoulder area.

A

rterial abnormalities. Cerebrovascular anomalies can include carotid artery abnormalities and absence, dilation, or narrowing of cerebral vessels. These anomalies, especially the carotid anomalies, can lead to progressive arterial occlusion and even stroke. Other neurological issues are noted in infancy and childhood.
[30]
[31]
[34]
[35]
[36]

C

ardiac abnormalities. Cardiac anomalies are most commonly coarctation of the aorta (coarctation is more proximal and affects longer segments), complex aortic arch anomalies, and ventricular and atrial septal defects.

A report of two patients with retro-orbital infantile hemangioma and arteriopathy suggested a possible new presentation of PHACE syndrome.
[40]
For patients with proptosis, globe deviation, and strabismus, an MRI/MRA is recommended. Further workup for PHACE may be needed on the basis of central nervous system (CNS) findings.

LUMBAR/PELVIS/SACRAL syndrome:

Infantile hemangiomas located over the lumbar or sacral spine may be associated with genitourinary, anorectal anomalies, or neurological issues such as tethered cord.
[41]
[42]
[43]
The following criteria have been used to describe segmental infantile hemangioma syndrome in the lumbar, pelvic, and sacral areas. This syndrome has been described in the literature using several acronyms.LUMBAR

L

ower-body hemangioma and other cutaneous defects.

U

rogenital anomalies or ulceration.

M

yelopathy.

B

ony deformities.

A

norectal malformations or arterial anomalies.

R

enal anomalies.

PELVIS

P

erineal hemangioma.

E

xternal genital malformations.

L

ipomyelomeningocele.

V

esicorenal abnormalities.

I

mperforate anus.

S

kin tag.

SACRAL

S

pinal dysraphism.

A

nogenital.

C

utaneous.

R

enal and urologic anomalies

A

ssociated with an angioma of

L

umbosacral localization.

Segmental lesions over the gluteal cleft and lumbar spine need to be evaluated with either ultrasound or MRI, depending on the age of the patient.

Infants with more than five infantile hemangiomas need to be evaluated for visceral hemangiomas. The most common site of involvement is the liver, in which multiple or diffuse lesions can be noted.
[44]
[45]
Often these lesions are asymptomatic, but in a minority of cases, symptoms such as heart failure secondary to large vessel shunts, compartment syndrome, or profound hypothyroidism can occur due to the expression of iodothyronine deiodinase.
[46]
Multiple or diffuse liver hemangiomas can occur in the absence of skin lesions. (Refer to the Benign Vascular Tumors of the Liver section of this summary for more information.)
Other rare potential complications of visceral hemangiomas, dependent on specific organ involvement, include gastrointestinal hemorrhage, obstructive jaundice, and CNS sequelae, caused by mass effects.

Treatment of infantile hemangioma

Pulsed dye laser therapy. Usually used for ulcerated infantile hemangiomas and residual lesions, such as telangiectasia after the proliferative period.
[47]
Pulsed dye laser therapy helps with pain from ulcerative infantile hemangiomas. The use of pulsed dye laser therapy as upfront treatment for infantile hemangiomas is controversial.

Excisional surgery. With the advent of new medical treatments, the use of surgery is reserved for ulcerated lesions, residual lesions, large periocular lesions that interfere with vision, and facial lesions with aesthetic impact that do not respond to medical therapy.
[48]

Propranolol therapy

Propranolol, a nonselective beta-blocker, is the first-line therapy for infantile hemangiomas. Potential mechanisms of action include vasoconstriction and/or decreased expression of VEGF and bFGF, leading to apoptosis.
[49]
[50]
Specific mechanisms of action are under investigation.

The use of propranolol was first noted in two infants treated for cardiac issues in Europe. A change in color, softening, and decrease in hemangioma size was noted. Since that time, the results of a randomized controlled trial have been reported.
[51]
In 2014, the U.S. Food and Drug Administration (FDA) approved the drug propranolol hydrochloride for the treatment of proliferating infantile hemangioma.

There are many other published reports about the efficacy and safety of propranolol.
[52]
[53]
[54]
[55]
[56]
Lack of response to treatment is rare. Propranolol therapy is usually used during the proliferative phase but has been effective in patients older than 12 months with infantile hemangiomas.
[57]

Evidence (propranolol therapy):

In a large industry-sponsored randomized trial, 456 infants aged 5 weeks to 5 months with a proliferating infantile hemangioma of at least 1.5 cm received either a placebo or propranolol (1 mg/kg per day or 3 mg/kg per day) for 3 or 6 months. After interim analysis of the first 188 patients who completed 24 weeks of trial treatment, the regimen of 3 mg/kg per day for 6 months was selected for the final efficacy analysis.
[51]
[Level of evidence: 1iDiv]

Of patients who received the selected regimen, 88% showed improvement by week 5, compared with 5% of patients who received the placebo.

Adverse events occurred infrequently.

In 635 infants with infantile hemangioma, the overall response rate was 91% after 2 mg/kg per day, with most patients showing regression and only 2% with side effects, none of which were severe.
[56]
[Level of evidence: 3iiiDiv]

A meta-analysis that evaluated 5,130 patients from 61 studies concluded that propranolol was more effective and safer than were other treatments for infantile hemangioma.
[58]

Airway infantile hemangioma lesions are rare; thus, there are limited prospective studies. A meta-analysis of 61 patients noted a trend of decreased treatment failure with increased dosing strategies, which is consistent with the use of higher doses of propranolol in these patients (3 mg/kg/day). The analysis also suggested that the concurrent use of steroids and propranolol may have reduced efficacy in patients with segmental airway hemangiomas, but previous treatment with steroids had no deleterious effect.
[59]
Additional prospective studies are needed to validate these findings.

Based on expert consensus panel recommendations and updated reviews, considerations for the administration of propranolol therapy include the following:
[60]
[61]
[62]

Initiation of treatment:

Treatment should be undertaken in consultation with a pediatric vascular anomaly specialist with expertise in the diagnosis and treatment of pediatric vascular tumors and in the use of propranolol in children. In accord with an expert consensus panel, it is suggested that hospitalization for initiation of oral propranolol be considered in the following circumstances:
[60]

Infant aged 5 weeks or younger (corrected for gestational age).Infant of any age with inadequate social support.Infant of any age with comorbid conditions affecting the cardiovascular or respiratory system, including symptomatic airway infantile hemangiomas.Infant of any age with conditions affecting blood glucose maintenance.

The pretreatment evaluation (inpatient or outpatient) includes the following:

History, with focus on cardiovascular and respiratory abnormalities (e.g., poor feeding, dyspnea, tachypnea, diaphoresis, wheezing, heart murmur) and family history of heart block or arrhythmia.Physical examination including cardiac and pulmonary assessment and measurement of heart rate and blood pressure.Consideration of an electrocardiogram, especially in children with heart rate lower than normal for age and history of arrhythmia or arrhythmia detected during examination.Family history of congenital heart disease or maternal history of connective tissue disease.

Dosing:

The dosing used is generally 1 mg/kg per day to 3 mg/kg per day divided into two or three doses. Patients are initially started at a dose of 0.5 mg/kg per day to 1 mg/kg per day and increased over time. Initially, dosing of three times per day is recommended for infants younger than 8 weeks and for patients with PHACE syndrome.

Monitoring:

Monitoring varies depending on the institution. However, oral propranolol peaks at 1 to 3 hours after administration and most centers measure heart rate and blood pressure 1 and 2 hours after each dose with initiation and then when the dose is increased by at least 0.5 mg/kg per day. Parent and patient education includes when to hold the medication, signs of hypoglycemia, feeding necessity through the night, and when to call the physician with issues, such as illness, that may interfere with oral intake or lead to dehydration or respiratory problems.

Contraindications:

Propranolol treatment is contraindicated in infants and children with the following:

Sinus bradycardia.Hypotension.Heart block greater than first degree.Heart failure.Asthma.Hypersensitivity.PHACE syndrome. PHACE syndrome with CNS arterial disease and/or coarctation of the aorta may be a relative contraindication. A decision to treat should be made in consultation with neurology and cardiology.

Adverse effects:

These complications have been reported in several studies, and severe complications have been rare.
[63]
The risk of these complications is increased in patients with comorbidities and concomitant diseases, including diarrhea, vomiting, and respiratory infections. The need for close monitoring and possible periods of drug discontinuation should be considered during periods of illness.

Rebound growth after propranolol therapy:

Rebound refers to the growth of infantile hemangiomas after propranolol cessation. A multi-institutional, retrospective review of 997 patients with infantile hemangiomas found a rebound rate of 25.3% in 912 patients with adequate data. On univariate analysis, the factors associated with rebound included discontinuation of treatment before age 9 months, female sex, location on head/neck, segmental pattern, and deep or mixed skin involvement. On multivariate analysis, only deep infantile hemangiomas and female sex were significantly related.
[64]

Other selective beta-blocker therapy

Because of the nonselective and lipophilic nature of propranolol with the ability to cross the blood-brain barrier, other beta-blockers are being used for the treatment of infantile hemangiomas. In two small comparison studies, there was no difference in efficacy between propranolol and atenolol.
[65]
[66]
In a retrospective study using nadolol, similar results were seen.
[67]
A prospective study of 76 infants treated with atenolol noted efficacy and safety similar to propranolol.
[68]
[Level of evidence: 3iiDiv] Additional studies are needed to assess differences between the toxicities of these agents and the toxicities of propranolol. There is some suggestion that the more selective beta-blockers have fewer side effects.
[69]

Corticosteroid therapy

Before propranolol, corticosteroids were the first line of treatment for infantile hemangiomas. They were first used in the late 1950s but were never approved by the U.S. FDA. Corticosteroid therapy has become less popular secondary to the acute and long-term side effects of steroids (gastrointestinal irritability, immunosuppression, adrenocortical suppression, cushingoid features, and growth failure).

Corticosteroids (prednisone or methylprednisolone) are used at times when there is a contraindication to beta-blocker therapy or as initial treatment while a patient is started on beta-blocker therapy.
[70]

Topical beta-blocker therapy

Topical beta-blockers are used mainly for the treatment of small, localized, superficial hemangiomas as an alternative to observation. They have also been used in combination with systemic therapy in complicated hemangiomas or to prevent rebound in a hemangioma being tapered off of systemic treatment.
[71]
[72]
[73]

The topical timolol that is used is the ophthalmic gel-forming solution 0.5%. One drop is applied to the hemangioma two to three times per day until stable response is achieved.

This treatment has limited side effects, but infants with a postmenstrual age of younger than 44 weeks and weight at treatment initiation of less than 2,500 grams may be at risk of adverse events, including bradycardia, hypotension, apnea, and hypothermia.
[74]
[75]
Close monitoring of temperature, blood pressure, and heart rate in premature and low birth weight infants with infantile hemangiomas at initiation of and during therapy with topical timolol is necessary.

Evidence (topical beta-blocker therapy):

In a multicenter, retrospective, cohort study, 731 children with predominantly superficial hemangiomas were treated with topical timolol 0.5% twice daily. Ninety-two percent of patients showed significant improvement in color and 77% showed improvement in size, extent, and volume. Topical timolol is generally well tolerated. However, data on its safety are limited.
[73]

Combined therapy for complicated hemangiomas

Combined therapy is considered either at initiation of treatment in complicated lesions in which there is functional impairment or organ compromise or used at the end of systemic therapy to prevent regrowth of the hemangioma rebound. Further investigation of efficacy and safety is needed for these regimens.

Evidence (combined therapy for complicated hemangiomas):

A prospective randomized study that compared propranolol and 2 weeks of steroid therapy with propranolol alone revealed a decrease in the size of the hemangioma at 2, 4, and 8 weeks but no statistical difference in the size at 6 months.
[76]

A prospective randomized study that compared timolol and propranolol with propranolol alone reported a decrease in color of the infantile hemangioma in the timolol group but no difference in overall size of the infantile hemangioma between the two treatment groups.
[77]

Treatment options under clinical evaluation for infantile hemangiomas

Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.

The following are examples of national and/or institutional clinical trials that are currently being conducted:

NCT02505971

(Nadolol Versus Propranolol in Children With Infantile Hemangioma)

:

This randomized, controlled, double-blinded study at Toronto Sick Kids is evaluating the efficacy and safety of both groups (nadolol and propranolol). Inclusion is for patients with hemangiomas that require systemic treatment.

NCT02913612

(Efficacy, Safety, and Pharmacokinetics of Topical Timolol in Infants With Infantile Hemangioma [TIM01])

:

This is a multicenter, double-masked, randomized, efficacy, safety, and pharmacokinetic study. Timolol maleate 0.25% is being compared with timolol maleate 0.5%.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

Congenital Hemangiomas

Congenital hemangiomas are benign vascular tumors that proliferate in utero. Development of these lesions is complete at birth. Histologically, these lesions are GLUT1 negative, unlike infantile hemangiomas. They are usually cutaneous, but can be found in the viscera. Complications include hemorrhage, transient heart failure, and transient coagulopathy.
[80]

To the clinician unfamiliar with these lesions, congenital hemangiomas can be difficult to diagnose. Diagnostic criteria include a purpuric lesion fully formed at birth, frequently with a halo around the lesion, with high flow noted on ultrasound imaging. Essential to the diagnosis is observation of decrease in size over time or stability. These lesions do not enlarge unless there is hemorrhage into the tumor.

Somatic activating mutations of GNAQ and GNA11 have been found to be associated with congenital hemangiomas.
[81]
Additional research is necessary to assess the significance of these findings, as this may aid in diagnosis and pathophysiology.

Congenital hemangiomas are divided into the following three forms:

Rapidly Involuting Congenital Hemangiomas (RICH).

These lesions are large high-flow lesions that are completely formed at birth but rapidly involute by 12 to 15 months. They can ulcerate and bleed and can cause transient heart failure and mild coagulopathy. After involution, usually some residual changes in the skin are present (refer to Figure 5).
[82]
[83]
[84]
[85]

Partial Involuting Congenital Hemangiomas (PICH).

These lesions are completely formed at birth and involute only partially.
[86]

Non-Involuting Congenital Hemangiomas (NICH).

These lesions are formed at birth and never involute. Depending on the location of the lesions and whether they cause functional impairment, the lesions may need to be removed surgically.
[87]
[88]

Benign Vascular Tumors of the Liver

In the literature, vascular liver tumors are usually classified as liver hemangioendotheliomas, a broad classification no longer in use. These tumors are classified according to their clinical characteristics and radiologic assessment.

Focal vascular lesions (congenital hemangiomas)

Focal lesions of the liver are usually congenital hemangiomas (RICH or NICH) (refer to Figure 6). RICH can present with symptoms of heart failure and mild to moderate coagulopathy.

Treatment options for focal vascular lesions include the following:

Supportive management.

Embolization for symptomatic shunting. These procedures need to be performed by interventional radiologists with expertise in vascular anomalies.
[89]

Surgery. Patients with focal symptomatic hepatic congenital hemangioma unresponsive to supportive management or radiological intervention may be surgical candidates for resection. This is a rare circumstance and needs to be evaluated by an interdisciplinary vascular anomaly team.

No medication has proven to be an effective treatment for these lesions, and infants need to be supported during this initial period until involution begins.
[45]
These lesions may be diagnosed prenatally. In rare situations, maternal treatment with medications such as steroids appeared to be effective but, more likely, natural involution may have been responsible.
[90]

Multiple liver lesions (infantile hemangiomas)

Multifocal hepatic lesions are infantile hemangiomas. Multifocal lesions may not need to be treated if the patient is asymptomatic, and they typically follow the same proliferative and involution course as cutaneous hemangiomas.
[45]
These lesions are monitored closely and if there is growth, propranolol therapy should be considered. If propranolol is needed, doses of up to 2 mg/kg per day are effective.

Treatment options for diffuse liver lesions may include the following:

Propranolol:

Beta-blockers are the most common treatment for diffuse and some multifocal infantile hemangiomas of the liver. Treatment doses of 2 to 3 mg/kg per day are indicated.
[51]

Chemotherapy:

Steroids, cyclophosphamide, and vincristine have been used to treat diffuse liver infantile hemangioma.
[45]
[93]
[94]

Transplant:

If a patient does not respond to medical management, a transplant may be indicated.
[95]
Transplantation is considered only for patients with severe diffuse lesions who have multisystem organ failure and there is insufficient time for effective pharmacologic therapy.

There have been isolated reports of malignancy in patients with diffuse hepatic infantile hemangiomas.
[96]
It is not clear if all cases were transformation of a benign lesion to a malignant phenotype; however, if the lesion does not respond to standard therapy, biopsy should be considered. Further evaluation and consensus is needed to assess whether these patients need to be monitored over a longer period of time with liver ultrasound. (Refer to the Angiosarcoma of the Soft Tissue section of this summary for more information.)

The differential diagnosis of vascular liver lesions always includes malignant liver tumors; thus, alpha-fetoprotein (AFP) should be included in the initial lab work. AFP can be elevated above baseline in congenital and infantile hemangiomas of the liver, but will rapidly fall to normal levels in 1 to 2 months, although there are no prospective studies investigating AFP elevation.
[97]
[98]
Some hypervascular hepatoblastomas in neonates with congestive heart failure have been mistaken for infantile hemangiomas. Other tumors in the differential diagnosis include angiosarcoma, metastatic neuroblastoma, and mesenchymal hamartomas. If there is any question about the diagnosis, a biopsy is recommended, although bleeding is a risk of the procedure.
[99]

Spindle Cell Hemangioma

Clinical presentation

Spindle cell hemangiomas, initially called spindle cell hemangioendotheliomas, often occur as superficial (skin and subcutis), painful lesions involving distal extremities in children and adults.
[100]
[101]
The tumors appear as red-brown or bluish lesions that can begin as a single nodule and develop into multifocal painful lesions over years. The lesions can be seen in Maffucci syndrome (cutaneous spindle cell hemangiomas occurring with cartilaginous tumors, enchondromas) and Klippel-Trenaunay syndrome (capillary/lymphatic/venous malformations), generalized lymphatic anomalies, lymphedema, and organized thrombus.
[102]
[103]

These tumors are well circumscribed, occasionally contain phleboliths, and consist of cavernous blood spaces alternating with areas of nodular spindle cell proliferation. A significant percentage of spindle cell hemangiomas are completely intravascular. The vein containing the tumor is abnormal, as are blood vessels apart from the tumor mass.
[102]
[103]

Treatment of spindle cell hemangioma

There is no standard treatment for spindle cell hemangioma because it has not been studied in clinical trials. Surgical removal is usually curative, although there is a risk of recurrence.
[102]
[103]

Epithelioid Hemangioma

Clinical presentation

Epithelioid hemangiomas are benign lesions that usually occur in the skin and subcutis but can occur in other areas such as the bone, with focal and multifocal lesions.
[102]
[104]
Epithelioid hemangiomas may be a reactive process, as they can be associated with local trauma and can develop in pregnancy. Patients usually present with local swelling and pain at the involved site. In the bone, they present as well-defined lytic lesions that involve the metaphysis and diaphysis of long bones.
[102]
[105]
They can have a mixed lytic and sclerotic pattern of bone destruction.

On pathologic evaluation, they have small caliber capillaries with eosinophilic, vacuolated cytoplasm and large oval, grooved, and lobulated nuclei. The endothelial cells are plump and are mature, well-formed vessels surrounded by multiple epithelioid endothelial cells within abundant cytoplasm. They lack cellular atypia and mitotic activity.
[102]
[104]
[105]

Treatment of epithelioid hemangioma

There is no standard treatment for epithelioid hemangioma because it has not been studied in clinical trials. Treatment consists of curettage, sclerotherapy, and resection, or rarely, radiation therapy.
[102]
[105]

Pyogenic Granuloma (Lobular Capillary Hemangioma)

Clinical presentation

Pyogenic granuloma, known as lobular capillary hemangioma, is a benign reactive lesion that can present at any age, including infancy, although it is most common in older children and young adults. They can present as single or multiple lesions.
[106]
[107]
[108]
[109]
These lesions can arise spontaneously, in sites of trauma, or within capillary and arteriovenous malformations. Pyogenic granulomas have also been associated with medications including oral contraceptives and retinoids. Most occur as solitary growths, but multiple (grouped) or rarely disseminated lesions have been described. These lesions appear as small or large, smooth or lobulated vascular nodules that can grow rapidly, sometimes over weeks to months and have a tendency to bleed profusely.

Histologically, these lesions are composed of capillaries and venules with plump endothelial cells separated into lobules by fibromyxoid stroma. Some untreated lesions eventually atrophy, become fibromatous, and slowly regress.

Treatment of pyogenic granuloma

Treatment often consists of full-thickness excision, curettage, or laser photocoagulation, but recurrence is common.
[110]
A small case series of four patients with acquired ocular surface pyogenic granulomas were treated with topical timolol 0.5% twice daily for 21 days. In all cases, complete resolution with no recurrence occurred for at least 3 months. More studies are needed to validate these findings.
[111]

Angiofibroma

Clinical presentation

Angiofibromas are rare, benign neoplasms in the pediatric population. Typically, they are cutaneous lesions associated with tuberous sclerosis, appearing as red papules on the face.

Treatment of angiofibroma

Excision of the tumor, laser treatments, and topical treatments, such as sirolimus, have been used.
[112]
[113]

Juvenile Nasopharyngeal Angiofibroma

Clinical presentation

Juvenile nasopharyngeal angiofibromas (JNA) account for 0.5% of all head and neck tumors.
[114]
Histologically, juvenile nasopharyngeal angiofibromas are benign vascular tumors but they can be locally destructive, spreading from the nasal cavity to the nasopharynx, paranasal sinuses, and orbit skull base, with intracranial extension. Some publications have suggested a hormonal influence on juvenile nasopharyngeal angiofibroma, with emphasis on the molecular mechanisms involved.
[115]
[116]

Treatment of juvenile nasopharyngeal angiofibroma

Surgical excision is the treatment of choice but this can be challenging because of the extent of the lesion. A single-institution retrospective review of juvenile nasopharyngeal angiofibromas identified 37 patients with lateral extension.
[117]
Anterior lateral extension to the pterygopalatine fossa occurred in 36 patients (97%) and further to the infratemporal fossa in 20 patients (54%). In 16 patients (43%), posterior lateral spread was observed (posterior to the pterygoid process and/or between its plates). The recurrence rate was 29.7% (11 of 37 patients). The recurrence rate in patients with anterior and/or posterior lateral extension was significantly higher than in patients with anterior lateral extension only.

Intermediate Tumors (Locally Aggressive)

Kaposiform Hemangioendothelioma and Tufted Angioma

Kaposiform hemangioendothelioma (KHE) and tufted angioma are rare vascular tumors that typically occur during infancy or early childhood but have been reported in adults. Both tumors are thought to be a spectrum of the same disease, because both can be locally aggressive and cause Kasabach-Merritt phenomenon, a serious life-threatening coagulopathy characterized by profound thrombocytopenia and hypofibrinogenemia. They are discussed here as a single entity, kaposiform hemangioendothelioma.

Incidence

The exact incidence of kaposiform hemangioendothelioma is unknown but is estimated to be 0.07 cases per 100,000 children per year.
[1]
[2]
[3]
The lesions affect both sexes equally, with most developing in the neonatal period, one-half presenting at birth, and others presenting during childhood or adulthood.
[4]

Pathology

Kaposiform hemangioendothelioma is characterized by sheets of spindle cells with an infiltrative pattern in the dermis, subcutaneous fat, and muscle. There are often areas of fibrosis, with dilated thin-walled vessels infiltrated around the areas of spindle cells. Mixed with these areas are nests of rounded epithelioid cells of vascular origin and aggregates of capillaries with round or irregularly shaped lumens containing platelet-rich fibrin thrombi. There is usually the presence of abnormal lymphatic spaces, either within or at the periphery of the lesion. The rate of mitosis is variable but usually low. Tufted angioma is characterized by multiple, discrete lobules of tightly packed capillaries (tufts) scattered in the dermis and sometimes in the subcutis, so called cannonball pattern.
[5]
Mitoses are rare.

The pathogenesis is poorly understood. There is some evidence that kaposiform hemangioendothelioma may be derived from lymphatic endothelium, as the spindle cell expresses the vascular markers CD31 and CD34, the vascular endothelial growth factor receptor-3, a receptor required for lymphangiogenesis, and the lymphatic markers D2-40 and PROX1.
[5]
[6]
[7]
There is no evidence of association with human herpesvirus 8 infection as is present in Kaposi sarcoma.
[7]

Clinical presentation

Kaposiform hemangioendothelioma most frequently involves the extremities and less frequently involves the trunk and head and neck area.
[3]
Most lesions involve the skin (refer to Figure 8). Deeper lesions (retroperitoneum, thoracic cavity, and muscle) can appear as a bluish-purpuric hue on the skin, whereas superficial lesions can be firm, purpuric or ecchymotic, and painful. Lesions are usually unifocal and growth is contiguous. Local lymph nodes may be involved, but they never metastasize. Rare multifocal presentations have been reported mostly in the bone.
[1]
[2]
[3]

Seventy percent of patients with kaposiform hemangioendothelioma develop Kasabach-Merritt phenomenon, which is a life-threatening complication characterized by profound thrombocytopenia (range, 3,000/µL–60,000/µL) and profound hypofibrinogenemia (<1 g/L). D-dimer and fibrin degradation products are elevated. Severe anemia can occur secondary to tumor sequestration. Severe hemorrhage is rare; however, trauma (biopsy, surgical procedure), ulceration, infection, or delay in initiating treatment may induce progression to disseminated intravascular coagulation and serious bleeding and death can occur. Aggressive replacement of blood products, especially platelets, can increase the size of the lesion, causing significant pain and should only be considered with active bleeding and under the direction of a vascular anomaly specialist.
[3]

Diagnostic evaluation

The diagnosis is based on the combination of clinical, histologic, and imaging features. Laboratory evaluation is essential for the diagnosis of Kasabach-Merritt phenomenon.
Whenever possible, histologic confirmation should be obtained, because prolonged therapy is often needed. However, if clinical and imaging findings are highly suggestive of the diagnosis, deferring biopsy is an option but needs to be planned with an interdisciplinary approach.

Magnetic resonance imaging is the imaging preference. T1-weighted sequences typically show a poorly circumscribed soft tissue mass with soft tissue and dermal thickening and diffuse enhancement with gadolinium. T2-weighted sequences show a diffuse increased signal, with stranding in the subcutaneous fat. Gradient sequences show mildly dilated vessels in and around the soft-tissue mass.
[3]

Treatment of kaposiform hemangioendothelioma and tufted angioma

Treatment varies according to severity; there is no evidence-based standard of care. An American and Canadian multidisciplinary expert panel published guidelines for the management of complicated kaposiform hemangioendothelioma.
[8]
A number of treatment therapies have been reported but none have been uniformly effective.
[9]
[10]

Propranolol therapy has been reported as a treatment option for kaposiform hemangioendothelioma. Its use is based on the positive results of propranolol for other more benign vascular tumors. Results have been mixed, with a report of improved effectiveness using higher doses of propranolol.
[18]
[19]
Preliminary results indicate that propranolol should be reserved for patients with kaposiform hemangioendothelioma without Kasabach-Merritt phenomenon and with smaller, less complicated lesions.

Secondary to promising case reports, case series and a prospective clinical trial, sirolimus may be considered an alternative first-line therapy for kaposiform hemangioendothelioma.
[14]
[15]
[20]
There are limited studies investigating its effect on kaposiform hemangioendothelioma/tufted angioma without Kasabach-Merritt phenomenon.

Reports that support the use of sirolimus include the following:

In a prospective study that assessed the efficacy and safety of sirolimus for the treatment of complicated vascular anomalies, 13 patients with kaposiform hemangioendothelioma were treated.
[21]

In patients with kaposiform hemangioendothelioma and Kasabach-Merritt phenomenon, ten of ten patients had a partial response, with normalization of their platelet count and fibrinogen at the end of six and 12 courses.

In three of three patients with kaposiform hemangioendothelioma without Kasabach-Merritt phenomenon, one patient with multifocal bony disease had disease progression while the other two patients revealed a partial response at the end of course 12. Side effects were minimal in this group of young patients and no patient with kaposiform hemangioendothelioma required a dose adjustment or was removed from study secondary to toxicity.

A single case report of a child with kaposiform hemangioendothelioma who developed recurrence of pain and fibrosis years after initial therapy and was treated with sirolimus for 26 months observed the following:
[20]

The patient's contracture and range of motion improved, the lesion shrank, and the child was well 2 years later.

In a multicenter, retrospective cohort study, 52 Chinese patients with progressive kaposiform hemangioendothelioma were analyzed. Thirty-seven patients (71%) had Kasabach-Merritt phenomenon. Those without Kasabach-Merritt phenomenon received sirolimus alone, and 21 of the patients with Kasabach-Merritt phenomenon received a combination of sirolimus and prednisone.
[22]

Additional studies are needed to determine the long-term efficacy and safety of sirolimus for the treatment of vascular tumors associated with Kasabach-Merritt phenomenon.

Surgical excision may be possible for lesions that are smaller, have failed medical management, or are life threatening. Embolization may be performed in conjunction with surgery or medical therapy; usually it is a temporizing measure.

The mortality associated with this tumor is primarily from the extensive coagulopathy associated with Kasabach-Merritt phenomenon.

Even with therapy, these lesions do not fully regress and can recur; worsened symptomatology (pain, inflammation) can occur with age, especially around the time of puberty.
[23]

Long-term effects include chronic pain, lymphedema, heart failure, and orthopedic issues.
[23]
These lesions prove to be a difficult dilemma for the practitioner because they have a varied clinical spectrum and response to therapy.

Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.

The following is an example of national and/or institutional clinical trial that is currently being conducted:

NCT02110069

(A Study to Compare Vincristine to Sirolimus for Treatment of High-Risk Vascular Tumors)

:

This is a study comparing vincristine with sirolimus for the treatment of high-risk kaposiform hemangioendothelioma. A multicenter adaptive study design determining efficacy (initially defined as the time to hematologic response) by comparing vincristine with sirolimus therapy while patients are on a steroid wean.

Pseudomyogenic Hemangioendothelioma

Incidence and outcome

Pseudomyogenic hemangioendothelioma is a rare, newly designated, distinct vascular tumor. It is characterized as an intermediate-grade tumor with moderately aggressive local spread and rare distant metastatic disease.

Pathology and biology

Pseudomyogenic hemangioendothelioma is characterized by loose fascicles of plump spindle and epithelioid cells with abundant eosinophils, cytoplasm, and coexpression of keratins and endothelial markers.
[1]
[2]
[3]
The etiology for this tumor is unclear, although a balanced translocation t(7;19) resulting in the SERPINE1-FOSB fusion gene was reported.
[4]

Clinical presentation and diagnostic evaluation

The tumor usually presents in young men aged 20 to 50 years.
[1]
[2]
Multifocal disease occurs in 70% of patients. Sites of involvement include the dermis, subcutis, and bones. Patients usually present with pain or a soft tissue mass.
[1]
[5]

Treatment of pseudomyogenic hemangioendothelioma

Most patients are treated with surgery, including amputation with multifocal bony disease.
[1]
In reported cases, chemotherapy has had limited response. Recently, the mammalian target of rapamycin (mTOR) inhibitors have been considered as treatment options.
[6]
[7]

Retiform Hemangioendothelioma

Pathology and clinical presentation

Retiform hemangioendotheliomas are slow growing, exophytic, flat tumors found in young adults and occasionally children.
[8]
They are usually located in the limbs and trunk. Histologically, they are located in the dermis and subcutaneous tissue. Vessels exhibit a pattern resembling the rete testis and are lined by protruding endothelial cells. They do not express lymphatic markers but stain positive for endothelial markers.
[9]

Prognostic factors

Local recurrences are common, but distinct metastases are extremely rare.
[9]

Treatment of retiform hemangioendothelioma

Surgical excision with adequate surgical tumor margins and monitoring for local recurrence is the treatment for this tumor. There are case reports of the use of radiation therapy and chemotherapy for inoperable and recurrent tumors.
[10]
[11]
[12]
[13]

Papillary Intralymphatic Angioendothelioma

Pathology and clinical presentation

Papillary intralymphatic angioendothelioma, also known as Dabska tumor, can occur in the adult and pediatric population.
[14]
The lesions occur in the dermis and subcutis on all body parts and there have been some reports of lymph node involvement. They can be large or small raised purplish firm nodules.

Pathologically, they reveal intravascular growth of well-differentiated endothelial cells in a columnar configuration. They have thickened hyaline walls with hobnailed endothelium. Vascular endothelial growth factor receptor type 3, a marker for lymphatic endothelium, is positive in most cases. There is minimal cytologic atypia.
[15]
Some are associated with vascular malformations.

Treatment of papillary intralymphatic angioendothelioma

Composite Hemangioendothelioma

Pathology and clinical presentation

Composite hemangioendothelioma is a very rare vascular tumor classified because of the combined benign and malignant vascular components. Usually, combined epithelioid and retiform variants are noted but some tumors have three components (epithelioid, retiform, and spindle cell).
[17]
Angiosarcoma foci have been noted. Pathology reveals positivity for CD31, factor VIII, and vimentin.
[17]
[18]
Rarely, D-240 is positive with a Ki-67 index of approximately 20%.
[17]

This tumor usually occurs in the dermis and subcutis of the distal extremities but has been found in other areas such as the head, neck, and mediastinum.
[17]
They have been reported in all age groups.
[17]

Prognostic factors

Treatment of composite hemangioendothelioma

Surgical removal is the treatment of choice, although radiation therapy and chemotherapy have been used for metastatic disease.
[19]
[20]

Kaposi Sarcoma

Pathology and clinical presentation

Kaposi sarcoma (KS) is a rare malignant vascular tumor associated with a viral etiology (human herpesvirus 8).
[21]
The skin lesions were first described in 1872 by Moritz Kaposi. The incidence has increased worldwide secondary to the HIV-AIDS epidemic. It is an extremely rare diagnosis in children. Epidemic and iatrogenic forms of Kaposi sarcoma in children result from profound acquired T-cell deficiency that results from HIV infection and rare immune disorders.

A retrospective study has investigated the presentation of Kaposi sarcoma in children in endemic areas of Africa. Children usually present with cutaneous lesions, lymphadenopathy, and intrathoracic and oral lesions. Cutaneous lesions initially appear as red, purple, or brown macules, later developing into plaques and then nodules.
[22]
[23]
[24]

Kaposi sarcoma is exceedingly rare in the pediatric population and is usually associated with immunocompromised states such as HIV infection or solid organ transplant.

Treatment of Kaposi sarcoma

Children with Kaposi sarcoma have responded to treatment with chemotherapy regimens, including bleomycin, vincristine, and taxanes, although there are no prospective clinical trials. Other treatment options have been based on adult studies (see below).

Because Kaposi sarcoma is rare in the pediatric population, there are no evidence-based studies. Even in adults, the evidence and quality of studies is inferior and it is difficult to recommend particular treatment regimens. Fifty-six Malawian children aged 3 to 12 years with Kaposi sarcoma were treated with six courses of vincristine, bleomycin, and oral etoposide. This was a high-risk population because 48 of the patients (86%) were HIV positive, of whom 36 (77%) were on antiretroviral therapy. Quality of life improved in 45 patients (80%). Eighteen patients (32%) had a complete remission. At 12 months, the overall survival rate was 71%, and the event-free survival rate was 50%.
[25]
[Level of evidence: 3iiA]

In a systematic review of treatment for classic Kaposi sarcoma, 26 articles published from 1980 to 2010 were reviewed; articles describing populations at high risk secondary to previous transplantation and endemic and epidemic Kaposi sarcoma were excluded.
[26]
All articles had a minimum of five patients per intervention. A greater than 50% decrease in the size of the lesions or lymphedema was considered a response. The quality of the articles was considered poor, primarily because of lack of uniform staging criteria and variable means of assessing response. The following response rates for systemic treatments were noted:

Malignant Tumors

Epithelioid Hemangioendothelioma

Incidence and outcome

This tumor was first described in soft tissue by Weiss and Enzinger in 1982. Epithelioid hemangioendotheliomas can occur at younger ages, but the peak incidence is in the fourth and fifth decades of life. The tumors can have an indolent or very aggressive course, with overall survival of 73% at 5 years. There are case reports of patients with untreated multiple lesions who have a very benign course compared with other patients who have a very aggressive course. Some pathologists have tried to stratify patients to evaluate risks and adjust treatment, but more research is needed.
[1]
[2]
[3]
[4]
[5]
[6]
[7]

The presence of effusions, tumor size larger than 3 cm, and a high mitotic index (>3 mitoses/50 high-power fields) have been associated with unfavorable outcomes.
[3]

Pathology and biology

A WWTR1-CAMTA1 gene fusion has been found in a large percentage of patients; less commonly, a YAP1-TFE3 gene fusion has been reported.
[1]
These fusions are not directly targetable with current medicines. Monoclonality has been described in multiple liver lesions, suggesting a metastatic process.

Histologically, these lesions are characterized as epithelioid lesions arranged in nests, strands, and trabecular patterns, with infrequent vascular spaces. Features that may be associated with aggressive clinical behavior include cellular atypia, one or more mitoses per 10 high-power fields, an increased proportion of spindled cells, focal necrosis, and metaplastic bone formation.
[3]

The number of pediatric patients reported in the literature is limited.

Liver:

Lung:

Pulmonary epithelioid hemangioendothelioma may be an asymptomatic finding on chest x-ray or be associated with pleuritic pain, hemoptysis, anemia, and fibrosis.

Bone:

Bone metastasis may be associated with pathologic fracture. On x-rays, they are well-defined osteolytic lesions and can be multiple or solitary.

Soft tissue:

Thirty percent of soft tissue cases are associated with metastases, and when present, can have a very aggressive course, with limited response to chemotherapy.

Skin:

Cutaneous lesions can be raised and nodular or can be warm red-brown plaques.

Treatment of epithelioid hemangioendothelioma

Treatment options for epithelioid hemangioendothelioma include the following:

Observation.

Surgery.

Immunotherapy.

Targeted therapy.

Chemotherapy.

For indolent cases, observation is warranted. For more aggressive cases, multiple medications have been used, including interferon, thalidomide, sorafenib, pazopanib, and sirolimus.
[10]
The most aggressive cases are treated with angiosarcoma-type chemotherapy. Surgery is used when possible. Liver transplantation has been used with aggressive liver lesions, both with and without metastases.
[3]
[11]
[12]
[13]
[14]

Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.

The following are examples of national and/or institutional clinical trials that are currently being conducted:

NCT03148275

(Trametinib in Treating Patients with Epithelioid Hemangioendothelioma That Is Metastatic, Locally Advanced, or Cannot Be Removed by Surgery)

:

This is a phase II trial assessing the efficacy of trametinib, with patient-reported outcomes as secondary aims.

NCT01532687

(Gemcitabine Hydrochloride With or Without Pazopanib Hydrochloride in Treating Patients With Refractory Soft Tissue Sarcoma)

:

This randomized phase II trial studies how well gemcitabine hydrochloride works with or without pazopanib hydrochloride in treating patients with refractory soft tissue sarcoma.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

Angiosarcoma of the Soft Tissue

Incidence

Angiosarcoma is a rare (accounting for 2% of sarcomas), aggressive, vascular tumor that can arise in any part of the body, but is more common in the soft tissue. Angiosarcoma has an estimated incidence of 2 cases per 1 million; in the United States, it annually affects approximately 600 people who are typically aged 60 to 70 years.
[15]

Angiosarcomas are extremely rare in children and it is unclear if the pathophysiology of this tumor is different in the pediatric population. Cases have been reported in neonates and toddlers, with presentation of multiple cutaneous lesions and liver lesions, some of which are GLUT1 positive.
[16]
[17]
[18]
[19]
Most angiosarcomas involve the skin and superficial soft tissue, although the liver, spleen, and lung can be affected; bone is rarely affected.

Risk factors

Established risk factors include vinyl chloride exposure, radiation exposure, and chronic lymphedema from any cause, including Stewart-Treves syndrome.
[20]

Pathology and biology

Angiosarcomas are largely aneuploid tumors. The rare cases of angiosarcoma that arise from benign lesions such as hemangiomas have a distinct pathway that needs to be investigated. MYC amplification is seen in radiation-induced angiosarcoma. KDR-VEGFR2 mutations and FLT4-VEGFR3 amplifications have been seen with a frequency of less than 50%.
[20]

Histopathologic diagnosis can be very difficult because there can be areas of varied atypia. The common feature is an irregular network of channels in a dissective pattern along dermal collagen bundles. There is varied cellular shape, size, mitosis, endothelial multilayering, and papillary formation. Epithelioid cells can also be present. Necrosis and hemorrhage are common. Tumors stain for factor VIII, CD31, and CD34. Some liver lesions can mimic infantile hemangiomas and have focal GLUT1 positivity. Nomenclature of these liver lesions has been difficult and confusing with use of terminology from 1971 (e.g., type I hemangioendothelioma: infantile hemangioma; type II hemangioendothelioma: low-grade angiosarcoma; type III hemangioendothelioma: high-grade angiosarcoma).
[17]

Treatment of angiosarcoma of the soft tissue

Treatment options for angiosarcoma of the soft tissue include the following:

Surgery (localized disease).

Radiation therapy (localized cutaneous disease in adults).

Surgery, chemotherapy, and radiation therapy (metastatic disease).

Localized disease is cured by aggressive surgery. Complete surgical excision
appears to be crucial for angiosarcomas and lymphangiosarcomas despite evidence
of tumor shrinkage in some patients who were treated with local or systemic therapy.
[18]
[21]
[22]
[23]
A review of 222 patients (median age, 62 years; range, age 15–90 years) showed an overall disease-specific survival (DSS) rate of 38% at 5 years. Five-year DSS was 44% in 138 patients with localized, resected tumors but only 16% in 43 patients with metastases at diagnosis.
[23]
Data on liver transplantation for localized angiosarcoma are limited.
[24]
[Level of evidence: 3iiA]

Localized disease, especially cutaneous angiosarcoma, can be treated with radiation therapy. Most of these reported cases are in adults.
[25]

Multimodal treatment with surgery, systemic chemotherapy, and radiation therapy is used for metastatic disease, although it is rarely curative.
[26]
Disease control is the objective in metastatic angiosarcoma, with published progression-free survival rates between 3 months and 7 months
[27]
and a median overall survival (OS) rate of 14 months to 18 months.
[28]
In both adults and children, 5-year OS rates between 20% and 35% are reported.
[18]
[19]
[29]

In a child diagnosed with angiosarcoma secondary to malignant transformation from infantile hemangioma, response to treatment with bevacizumab, a monoclonal antibody against vascular endothelial growth factor, combined with systemic chemotherapy, has been reported.
[16]
[26]
A report of eight cases of liver angiosarcoma in children highlighted the misuse of the term hemangioendothelioma and the importance of early diagnosis and treatment of these tumors.
[30]

Treatment options under clinical evaluation for angiosarcoma of the soft tissue

Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.

The following are examples of national and/or institutional clinical trials that are currently being conducted:

ARST1321 (NCT02180867)

(Radiation Therapy With or Without Combination Chemotherapy or Pazopanib Hydrochloride Before Surgery in Treating Patients With Newly Diagnosed Nonrhabdomyosarcoma Soft Tissue Sarcomas That Can be Removed by Surgery [PAZNTIS])

NCT01532687

(Gemcitabine Hydrochloride With or Without Pazopanib Hydrochloride in Treating Patients With Refractory Soft Tissue Sarcoma)

:

This randomized phase II trial studies how well gemcitabine hydrochloride works with or without pazopanib hydrochloride in treating patients with refractory soft tissue sarcoma.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

Special Considerations for the Treatment of Children With Cancer

Cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975.
[1]
Children and adolescents with
cancer should be referred to medical centers that have a multidisciplinary team
of cancer specialists with experience treating the cancers that occur during
childhood and adolescence. This multidisciplinary team approach incorporates the skills
of the primary care physician, a surgeon experienced in vascular
tumors, a pathologist, radiation oncologists, pediatric oncologists,
rehabilitation specialists, pediatric nurse specialists, social workers, and
others to ensure that children receive treatment, supportive care, and
rehabilitation that will achieve optimal survival and quality of life.
(Refer to the PDQ summaries on Supportive and Palliative Care for specific information about supportive care for children and adolescents with cancer.)

Guidelines for pediatric cancer centers and their role in the treatment of
pediatric patients with cancer have been outlined by the American Academy of
Pediatrics.
[2]
At these pediatric cancer centers, clinical trials are
available for most types of cancer that occur in children and
adolescents, and the opportunity to participate in these trials is offered to
most patients and families. Clinical trials for children and adolescents with
cancer are generally designed to compare potentially better therapy with
therapy that is currently accepted as standard. Most of the progress
made in identifying curative therapies for childhood cancers has been achieved
through clinical trials. Information about ongoing clinical trials is
available from the NCI website.

Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2010, childhood cancer mortality decreased by more than 50%.
[1]
Childhood and adolescent cancer survivors require close monitoring because cancer therapy side effects may persist or develop months or years after treatment. (Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood vascular tumors. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

be discussed at a meeting,

be cited with text, or

replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Childhood Vascular Tumors Treatment are:

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

Permission to Use This Summary

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Based on the strength of the available evidence, treatment options may be described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

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